stemi-optimal antiplateletantithrombotic in emergency dep

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Advancing the Standard of Care: Cardiovascular and Neurovascular Emergencies January 20

ST-segment Elevation Myocardial Infarction (STEMI): Optimal Anti-platelet and Anti-thrombotic Therapy in the Emergency Department

ST-segment ElevationMyocardial Infarction(STEMI): Optimal Anti-platelet and Anti-thromboticTherapy in the EmergencyDepartment

James W. Hoekstra, MD

Professor and Fredrick Glass Chairman; Department of

Emergency Medicine, Wake Forest University,

Winston Salem, NC

Objectives:

1. Participants should be familiar with the 2007 Focused

Update on STEMI and its relationship to the 2004 ACC/

AHA guidelines for the treatment of ST Elevation MI

(STEMI).

2. Participants should understand the clinical decision-

making factors needed to determine the optimum

reperfusion therapy for STEMI.

3. Participants should understand the recent clinical trial

evidence and rationale behind the use of clopidogrel and

enoxaparin in the treatment of STEMI with fibrinolysis.

4. Participants should understand the recent clinical trialevidence supporting the use of clopidogrel, prasugrel, and

bivalirudin in the treatment of STEMI with primary PCI.

Introduction

When minutes count, and time is muscle, emergency

physicians have the opportunity to make a crucial impact

on morbidity and mortality by applying appropriate therapy

in a very time-efficient manner in the treatment of ST-

segment elevation myocardial infarction (STEMI). The

2004 American College of Cardiology/American Heart

Association (ACC/AHA) Guidelines for the treatment of

STEMI and the 2007 ACC/AHA Focused Update (Focused

Update) for STEMI outline the recommendations for

the emergency department (ED) management of STEMI,

including anti-ischemic, anti-thrombotic, and fibrinolytic

versus catheter-based reperfusion therapy.1,2These guidelines

were promulgated in an effort to standardize and optimize

the evaluation, diagnosis, and management of patients with

STEMI and to provide physicians with a framework for clinical

decision-making. They have become the cornerstone of man

ED protocols for the treatment of STEMI which are cruci

to providing efficient care in the ED and seamless transitio

for patients to the cardiac catheterization laboratory or CCU

Within a few months of the 2007 Focused Update publicatio

however, new clinical trials data were released and publishe

which added significantly to the treatment of STEMI, an

may change initial ED management of this disease procesSpecifically, new clinical trials data support changes in th

dosing and application of anti-platelet and anti-thromb

therapy in the treatment of STEMI.

The Choice of Reperfusion Therapy in STEMI:

Fibrinolytics versus PCI

The pathophysiology of STEMI is initiated by the endotheli

rupture of an atherosclerotic coronary artery plaque. Plaq

rupture leads to platelet aggregation, platelet activatio

fibrin deposition, and downstream myocardial ischemia annecrosis. Downstream necrosis is time dependent, with

wave front of necrosis developing from the subendocardiu

and extending transmurally to the epicardium over time. Th

longer the period of necrosis the higher the chance of hea

failure and death. For every 30 minute duration of ischem

there is an 8-10% increase in mortality.3 Reperfusion therap

with dissolution or removal of the intracoronary thrombu

provides the best chance for mortality reduction. The Focus

Update gives primary percutaneous coronary interventio

(PCI) a Class IA recommendation for reperfusion, as long

it can be accomplished with a first medical contact to balloo

inflation time of 90 minutes or less.2 Fibrinolysis, which is leeffective than PCI in head-to-head trials, is given a Class I

rating as an alternative to primary PCI, as long as PCI cant b

accomplished within 90 minutes.

There is a distinct gray zone, however, in patients in who

the choice must be made between timely fibrinolysis vers

minimally delayed primary PCI. This decision is often ma

in the context of an inter-hospital transfer. The emergen

physician must decide between fibrinolysis within 30 minut

followed by transfer, versus transfer for PCI, knowing that th

chance of a door-to-balloon time of 90 minutes is remote.

the National Registry of Myocardial Infarction, the percentaof patients meeting the 90 minute window with a transfer fro

one hospital to another was less than 4%.4 Factors whic

preclude waiting for PCI include young age, anterior M

and early ( 120 minutes.


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January 2010 Advancing the Standard of Care: Cardiovascular and Neurovascular Emergencies

2 ST-segment Elevation Myocardial Infarction (STEMI): Optimal Anti-platelet and Anti-thrombotic Therapy in the Emergency Department

Whichever reperfusion strategy is chosen, it is important to

maximize the effectiveness of that therapy by applying not

only speed, but appropriate anti-platelet and anti-thrombin

adjuncts. The recommendations for these therapies differ

with the reperfusion method chosen. Appropriate protocol

development demands maximization of the effectiveness of

anti-platelet and anti-thrombin agents with each reperfusion

choice.

Anti-platelet and Anti-thrombin Therapy with Fibrinolysis

If fibrinolysis is chosen as the reperfusion strategy, appropriate

anti-platelet adjuncts include aspirin, clopidogrel, and

glycoprotein IIb/IIIa (GPI) receptor blockers. All have been

investigated in large multicenter clinical trials, but only

aspirin and clopidogrel have been incorporated as Class I

recommendations in the ACC/AHA Guidelines in patients

treated with fibrinolysis.1,2 Specifically, aspirin 325 mg p.o. is

indicated at patient presentation regardless of the reperfusionstrategy, while clopidogrel 300 mg is indicated as the loading

dose administered in the ED with fibrinolysis.

Clopidogrel is an oral anti-platelet agent which binds to

platelets at the P2Y

12 receptor site, and inhibits platelet

activation through the ADP-mediated pathway. The

Focused Update gives clopidogrel 75 mg daily a Class

IA recommendation for STEMI. The 300 mg load is

recommended with fibrinolysis (Class IIaC). The CLARITY

trial investigated the effectiveness of a 300 mg loading dose

of clopidogrel, in conjunction with fibrinolytic therapy, in the

treatment of STEMI.6

The CLARITY trial randomized 3491STEMI patients to a clopidogrel 300 mg load, and 75 mg per

day versus placebo, initiated in the ED. The primary outcome

of death, MI, and target vessel occlusion at angiography was

reduced 36% (p=0.00000036) in the clopidogrel group, offset

by only a 0.3% increase in bleeding. Death, MI and recurrent

ischemia at 30 days were reduced 20% with clopidogrel

(p=0.026). In the patients who went on to PCI after initial

fibrinolytic therapy, there was a 46% reduction in death, MI,

and stroke in the patients treated with clopidogrel (p=0.008).

These results were further supported by the COMMIT trial,

which randomized 45,852 STEMI patients (recruited in Asia)

who were treated with fibrinolytics or medical management,to 75 mg q.d. (no loading dose) of clopidogrel versus placebo.7

In the COMMIT trial, clopidogrel was associated with a

9% relative reduction in death, recurrent MI, and stroke

(p=0.002). Clopidogrel should be added to STEMI treatment

algorithms in the ED, if not already in the care pathway, with

a loading dose of 300 mg given in the ED.

The Focused Update for STEMI recommends the

administration of an anti-thrombin as an adjunct to

reperfusion therapy, initiated in the ED, either in

conjunction with fibrinolytic therapy or in preparation

for primary PCI. The focused update gives unfractionated

heparin a Class IC recommendation, and enoxaparin a

Class IA recommendation. The EXTRACT TIMI 25 trial

compared enoxaparin (30 mg IVP, and 1 mg/kg subcutaneous)to unfractionated heparin (weight based dosing) in 20,478

patients treated with a variety of fibrinolytics for STEMI.8

The trial was a double-blind, double-dummy design, and

carried out mostly in Europe. The primary outcome of

death and MI at 30 days was reduced 17% (p


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Anti-platelet and Anti-thrombin Therapy with Primary PCI

Anti-platelet agents recommended by the Focused Update in

the treatment of STEMI by primary PCI include aspirin,

clopidogrel, and glycoprotein IIb/IIIa inhibitors (GPI). Recent

evidence supports a loading dose of 600 mg of clopidogrelwith

primary PCI, and other trials support the use of prasugrel as a

new alternative to clopidogrel with primary PCI.

Clopidogrel, which is given as a 300 mg bolus with fibrinolytics,

should be given as a 600 mg bolus prior to primary PCI. This

dose is based on the ARMYDA 2 trial9and is supported by

the current ACC/AHA PCI guidelines.10 The ARMYDA 2

trial was a small 255 patient PCI trial investigating clopidogrel

300 mg versus clopidogrel 600 mg, given as a bolus before PCI.

Although the patients in ARMYDA 2 were not high risk for

adverse outcomes, there was a robust 67% reduction in death,

MI, and urgent target vessel revascularization in the patients

receiving the 600 mg clopidogrel loading dose (p=0.041). The

recently presented multicenter CURRENT trial investigatedclopidogrel 300 mg versus 600 mg head-to-head in 25,000

patients, 29% of which underwent primary PCI for STEMI.

Clopidogrel was initiated upstream, in patients destined for

PCI. The 600 mg load was associated with a lower rate of the

combined endpoint of 30 day death, MI, and stroke (p=0.06),

while stent thrombosis was reduced 42% (p=0.002)(Table 2).11

These trials support the PCI guideline recommendation for

administration of clopidogrel 600 mg upstream prior to PCI

for STEMI.

Prasugrel is a new FDA approved oral P2Y

12platelet inhibitor

which is more potent than clopidogrel. It was recentlyinvestigated in the TRITON-TIMI 38 trial where it was

shown to be more effective than clopidogrel in reducing death

and MI, but its effects were offset by bleeding, especially in

patients with prior stroke, advanced age, or low body weight

The STEMI portion of TRITON TIMI 38 was recent

published, demonstrating a similar reduction in death and M

in patients receiving prasugrel 60 mg load versus clopidogr

300 mg load during primary PCI for STEMI.13 The ischem

benefits of prasugrel over clopidogrel were maintained

STEMI patients (Figure 1), while the bleeding effects were n

statistically significantly different in the two groups. Prasugr60 mg remains a viable option as a substitute for clopidogr

300 mg loading in STEMI patients undergoing PCI. It h

not yet been tested head-to-head versus a clopidogrel 600 m

loading dose.

Since the Focused Update was published, another ant

thrombin has been investigated in the treatment of STEM

with primary PCI. The HORIZONS trial14 investigated th

use of heparin plus a GPI versus bivalirudin with provision

GPI therapy in 3602 STEMI patients undergoing primary PC

The primary outcome of the trial was the net clinical outcom

of death, MI, stroke, or urgent intervention plus major bleedinat 30 days. Bivalirudin monotherapy resulted in no differen

in ischemic endpoint, but a significant 40% reduction (8.3

versus 4.9%, p


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January 2010 Advancing the Standard of Care: Cardiovascular and Neurovascular Emergencies

4 ST-segment Elevation Myocardial Infarction (STEMI): Optimal Anti-platelet and Anti-thrombotic Therapy in the Emergency Department

Efficacy endpoints at 30 days

*ARC def/probable

0

2

4

6

8

10

All Death MI UTVR Stent

Thrombosis*

CV Death/

MI

CV Death/

MI/UTVR

CV Death/

MI/Stroke

Proportionofpopulatio

n(%)

p=0.04

p=0.01

p=0.13 p= 0.008

p=0.004 p=0.02p=0.002

Clopidogrel

Prasugrel

Figure 1: TRITON-TIMI 38 STEMI trial results: Reduction in ischemic endpoints with prasugrel 60 mg loadversus clopidogrel 300 mg load upstream prior to PCI for STEMI. Adapted and reprinted with permission

from Montalescot et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary

intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial.

Lancet 2009; 373:723-731.

Figure 2: Results from the HORIZONS trial 1 year data: Reduction in mortality with bivalirudin versus

heparin plus a GPI. Adapted and reprinted with permission from Stone et al. N Engl J Med 2008;358:2218-

30. Bivalirudin during Primary PCI in Acute Myocardial Infarction. Presented at: Transcatheter Cardiovascular

Therapeutics meeting (TCT 2008); 17, 2008; Washington, DC. October 12.

HORIZONS-AMI: 1-Year All-Cause Mortality

Number at risk:

Bivalirudin alone

Heparin + GP IIb/IIIa

1800 1705 1684 1669 1520

1802 1678 1663 1646 1486

Mortality,

%

0

1

2

3

4

5

Time in Months

0 1 2 3 4 5 6 7 8 9 10 11 12

Bivalirudin alone (n=1800)

Heparin + GP IIb/IIIa (n=1802) 4.8%

3.4%

Diff [95%CI] = -1.5% [ -2.8,-0.1]

HR [95%CI] = 0.69 [0.50, 0.97] P=.029

3.1%

2.1%

= 1.0%

P=.049

= 1.4%


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Synthesizing these data, it appears that the optimum ED

management of STEMI for patients destined to undergo

primary PCI includes clopidogrel 600 mg loading dose (or

prasugrel 60 mg), heparin 4000 units IVP, and rapid transfer

to the cardiac catheterization laboratory. The utilization of

GPI or bivalirudin in the catheterization laboratory can be

left to the cardiologist, and will not be hindered by emergency

physician upstream management (Table 3).

References

1. Antman EM, Anbe DT, Armstrong, PW, et al. ACC/AHA guidelinefor the management of patients with ST-elevation myocardialinfarction: a report of the task force on practice guidelines: Executivsummary. Available at www.circulationaha.org. or www.acc.org/clinicguidelines/stemi.index.pdf.

2. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Updateof the ACC/AHA 2004 Guidelines for the Management of Patients

With ST-Elevation Myocardial InfarctionJACC 2008;51(2): 210-247available on line at acc.org.clinical/guidelines/stemi.index.pdf.

3. Pinto DS, Kirtane AJ, Nallamathu BK, et al. Hospital delays inreperfusion for ST-elevation myocardial infarction: implications whenselecting a reperfusion strategy. Circulation 2006;114:2019-2025.

4. Nallamothu BK, Bates ER, Heron J, et al. Times to treatmentin transfer patients undergoing primary percutaneous coronaryintervention in the United States: National Registry of MyocardialInfarction (NRMI)-3/4 analysis. Circulation 2005;111:7617.

5. Antman EM, Anbe DT, Armstrong PW, et al. 2004 ACC/AHAguidelines for the management of patients with ST-elevation myocardinfarction--executive summary. J Am Coll Cardiol. 2004;44:671-719

6. Sabatine MS, Cannon CP, Gibson M, et al. Addition of clopidogrelto aspirin and fibrinolytic therapy for STEMI. N Engl J Med.

2005;352:1179-1189. 7. The COMMIT trial investigators: Addition of clopidogrel to aspirin

in 45,852 patients with AMI: a randomized placebo controlled trial.Lancet 2005;366:1607-1621.

8. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versusunfractionated heparin with fibrinolysis for ST elevation MI(EXTRACT TIMI 25 trial). N Eng J Med 2006;354:1477-1488.

9. Patti G, Colonna G, Pescari V. Randomized Trial of High LoadingDose of Clopidogrel for Reduction of Periprocedural MyocardialInfarction in Patients Undergoing Coronary Intervention - ResultsFrom the ARMYDA-2 (Anti-platelet therapy for Reduction ofMYocardial Damage during Angioplasty) Study. Circulation2005:111;2099-2106.

10. Smith SC, Feldman TE, Hirschfeld JW, et al. A Report of theAmerican College of Cardiology/American Heart Association Task

Force on Practice Guidelines ACC/AHA guidelines for percutaneouscoronary intervention. Available at www.acc.org/clinical/guidelines/percutaneous/update/index_rev.pdf.

11. Mehta S, et al: CURRENT Trial results, presented at the EuropeanSociety of Cardiology meeting, September, 2009.

12. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versusClopidogrel in Patients with Acute Coronary Syndromes. N Engl JMed 2007;357:2001-2015.

13. Montelescot G, Wiviott S, Braunwald E, et al. Prasugrel compared wclopidogrel in patients undergoing percutaneous coronary interventiofor ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009; 373:723-731.

14. Stone G, et al. HORIZONS trial results. Presented at the TranscatheTherapeutics Meeting, Washington, DC, November, 2007 .

15. Stone G, et al: HORIZONS One Year Results, presented at TCTannual meeting, Washington, DC, November, 2008.

Table 3. Summary recommendations for anti-platelet and anti-

thrombin recommendations for STEMI treated by primary PCI.

1. Targeted ED protocol and collaboration

2. ASA immediately (325 mg)

3. Morphine sulfate, nitrates, -blockers by mouth

(intravenous if tachycardia or hypertension present)

4. P2Y12 Platelet Inhibitor:

Clopidogrel 600 mg by mouth, 75 mg daily

OR

Prasugrel 60 mg by mouth, 10 mg daily

5. Anti-thrombin:

Heparin weight-based dosing (max 4,000U) for PCI

(transition to bivalirudin?)

6. PCI in less than 90 minutes, prefer this from time of first

medical contact

7. GPI inhibition in cardiac catheterization lab (provisional

with bivalirudin)

Conclusions

The CLARITY, COMMIT, EXTRACT, HORIZONS,

CURRENT, and TRITON-TIMI 38 trials are only a few

examples of the many recent clinical trials involving the

care of patients with STEMI. Like many past clinical trials,

these recent trials answer some clinical questions, but raise

others. These trials must be interpreted in the light of

current practice, with emphasis on applicability to the ED

or in-patient hospitalist practice. Lessons from these trials

may change practice, or strengthen the data behind current

practice patterns. Emergency physicians and hospitalists must

remain vigilant to the results of these and other trials to keep

up-to-date and provide cutting edge care for STEMI patients.

stemi-optimal antiplateletantithrombotic in emergency dep

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